tbuckley/cabot-search huggingface dataset:
Methylated ctDNA as a biomarker for detecting previously undetectable clinically significant somatic mutations.
Authors: Patrick Peiyong Ye, Brian D. Woodward, Sydne Langpap, Robb Viens, Katherine Shelburne, Wen Zhou, Joyce Zhu, Jan Wignall, Naomi Searle, Matthew Gordon Varga, Gary A. Palmer, David Tsao, Oguzhan Atay, Hatim Husain
Journal: Journal of Clinical Oncology (2023)

e15020 Background: Treatment selection liquid biopsies can be re-run upon clinical progression to identify the new clinically significant somatic mutations that might be contributing to resistance to therapy or that can help guide the selection of an alternative therapy. However, there are not currently any biomarkers or tests that suggest an increased likelihood for the detection of new, i.e. previously undetected, clinically significant somatic mutations in a subsequent treatment selection liquid biopsy assay. Methods: We explored whether a methylation-based liquid biopsy could indicate when new clinically significant alterations are more likely to be detected in a treatment selection liquid biopsy. As part of a retrospective study of metastatic lung cancer patients (N = 75 new treatment starts), both a treatment selection assay and a therapy monitoring methylation assay were performed on plasma collected pre-treatment for a subset of patients that underwent at least two separate treatment regimens. By quantifying the number of methylated ctDNA molecules at &gt; 500 genomic locations, the methylation assay assessed the total burden of methylated ctDNA (represented as tumor methylation score), as well as the percent of methylated molecules originating from newly methylated genomic loci, representing a change in the methylation profile. Results: When the methylation assay detected at least a 2x increase in the tumor methylation score, indicating a significant increase in the fraction of ctDNA present in the patient’s blood, new clinically significant somatic mutations (including actionable ERBB2 alterations) were found 83% of the time. This appeared to be more frequent than among patients without an increase in tumor methylation score, where new clinically significant somatic mutations were found 33% of the time. Importantly, when the increase in the methylation score was coupled with a significant change in the methylation profile, new clinically significant mutations were identified in 100% of patients. Conclusions: The preliminary data suggests that an overall increase in methylated ctDNA, in combination with a significant change in methylation profile, is correlated with detecting new, previously undetected clinically significant somatic mutations in a treatment selection assay. Leveraging this methylated ctDNA assay may inform clinicians as to when to run another treatment selection assay, thereby potentially identifying the appearance of clinically significant somatic mutations which could influence clinical decision making and affect patient clinical outcomes.
Implementation of 3 month therapy for stage III colon cancer in a large community practice.
Authors: Victoria Shklar, Martin Christopher Barnes, Hira Chaudhary, Janta Ukrani, Harry Staszewski
Journal: Journal of Clinical Oncology (2023)

e15653 Background: Standard adjuvant chemotherapy for Stage III colon cancer comprises FOLFOX (5 FU/oxaliplatin(OX)/leucovorin) or CAPOX (capecitabine (CAP), OX) for six months. Toxicity from OX impacts quality of life and persists beyond treatment. In March 2018, the NEJM published the IDEA study demonstrating that 3 month FOLFOX or CAPOX was non-inferior to 6 month with less toxicity, specifically in low risk (LR) populations ( &lt; T4 and/or &lt; N2). National guidelines then incorporated 3 month options. We profiled adoption of these regimens at NY Cancer &amp; Blood Specialists after updated guidelines were published. By examining guideline compliance we hope to improve the treatment of patients with Stage III. Methods: We retrospectively reviewed all 234 electronic charts of patients presenting for management of Stage III after the NEJM publication. Substage, duration of therapy, and reasons for delay or discontinuation were analyzed. Results: 234 patients underwent surgery and presented for consideration of adjuvant therapy. 32 (14%) had stage IIIA, 164 (70%) had IIIB, and 32 (14%) had IIIC. 96 (41%) had high risk (HR) disease, 11/96 (11%) patients were recommended 3 months of therapy and 81/96 (84%) were recommended 6 months. 138 patients (59%) were LR, of which 48/138 (35%) were recommended 3 months of therapy and 81/138 (59%) were recommended 6 months. Thus, 59/234 (25%) patients were recommended to proceed with only 3 months of therapy (see table). 215/234 patients (92%) received adjuvant therapy (2 died prior to treatment start, 8 were not treated due to age or poor performance status, 1 had financial issues, 6 refused, 2 were lost to follow-up). 57 patients received or were planned for CAPOX, 114 for FOLFOX, 41 for CAP, and 9 for 5-FU. Treatment started a mean of 7 weeks post-op. 108/215 patients (50%) required dose interruptions, while 85 (40%) required dose reductions and 14 (7%) switched regimens. 164 patients (76%) completed the full duration with some therapy. 41 patients had a recurrence/progression (34 actually received adjuvant therapy). Conclusions: Among 234 patients with stage III colon cancer intended for adjuvant therapy in a large community practice, 25% were planned for or treated with 3 months vs 6. Of those that initiated therapy, 76% completed treatment. The results of the IDEA trial have influenced decision making for community oncologists. While only a quarter implemented shorter durations of treatment, we expect that this rate will increase as improved patient outcomes are demonstrated. [Table: see text]
Phase II trial of adjuvant de-escalated radiation + adjuvant nivolumab for intermediate-high risk P16+ oropharynx cancer.
Authors: Heath Devin Skinner, Dan Paul Zandberg, Adam Raben, Shaum Sridharan, Mark Kubik, Jose Zevallos, Seungwon Kim, Umamaheswar Duvvuri, James Ohr, William E. Gooding, Robert L. Ferris
Journal: Journal of Clinical Oncology (2023)

6014 Background: Treatment de-intensification for resected, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is an area of active investigation, with a goal of providing a less toxic adjuvant regimen compared to the current standard of care 66 Gy of radiation (RT) combined with concurrent cisplatin defined in recently reported as Arm D of the ECOG3311 trial. Here, the programmed death 1 (PD-1) antibody nivolumab was added to de-intensified RT in high risk, resected HPV+ OPC. Methods: Eligible patients included transorally resected pathologic stage III or IVA HPV+ OPSCC using p16 immunohistochemistry, featuring high-risk neck disease factors (gross extracapsular extension &gt;1mm or ≥5 positive lymph nodes) to mirror ECOG3311 Arm D patients accrued. Positive margin status was excluded except by PI approval. Postoperative treatment consisted of accelerated fractionation RT (50 Gy over 4 weeks) concurrent with nivolumab at 240 mg every 2 weeks, followed by 6 months of adjuvant nivolumab biweekly or monthly. The primary endpoint was progression-free survival (PFS). Swallowing and quality of life patient reported outcome (PRO) measures were collected at baseline and defined intervals after treatment. Results: Forty-one patients (n=41) were accrued and were analyzed. Forty of 41 patients remain alive with a median follow-up of 30 months (range 1 – 49 months). The probability of 3-year overall survival is 97% (95% CI = 90% - 100%) and the probability of 3-year PFS is 86% (95% CI = 68% - 100%). Two patients developed recurrent disease, one of whom died. One patient developed isolated metastasis while a second developed local, regional, and distant metastasis. The most common adverse grade ≥3 adverse events were lymphocytopenia (n=24), dysphagia (n=2) and oral mucositis (n=2). One grade 4 sepsis/multi-organ failure was reported. Comparison of PRO results with those observed in ECOG3311 trial are underway and will be reported. Conclusions: De-intensification of adjuvant treatment adding nivolumab to RT is tolerable and demonstrates favorable clinical outcome for high-risk, resected, HPV+ HNSCC patients. Further targeted immunotherapy combinations are warranted. Clinical trial information: NCT03715946 .
A phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1).
Authors: Ira Seth Winer, Amita Patnaik, Minal A. Barve, Shivaani Kummar, Erin Lynn Schenk, Patricia LoRusso, Oladapo O. Yeku, Siqing Fu, Nadine Jahchan, Matthew Myers, Linda Liang, Denise Deegan, Lynnae Jackson, Yunfeng Li, Len Reyno, Marc Charles Chamberlain
Journal: Journal of Clinical Oncology (2023)

2523 Background: This study aimed to characterize the safety of PY159 (an agonist antibody to TREM1 that reprograms immunosuppressive intratumoral myeloid cells) as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors, including subjects refractory to immune checkpoint inhibitors. Methods: Two strata were evaluated, PY159 as a single agent and in combination with pembrolizumab, using an accelerated 3+3 dose escalation study design. Dosing was intravenous once every 3 weeks. Disease assessment by RECIST 1.1 was performed every 6 weeks. The single-agent stratum included 7 dose levels of PY159 (range, 0.01–10 mg/kg). The combination stratum included 4 dose levels of PY159 (range, 0.3–10 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM1 expression by immunohistochemistry. Based on preclinical immunohistochemistry data, HR+ HER2– and triple-negative breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, and gynecologic cancers were studied. Results: Thirty-seven subjects (median age 65 years; range 29–86 years; 22 female and 15 male) with an ECOG PS &lt;2 were enrolled and all but 5 were RECIST-evaluable (3 withdrew consent, 1 sustained a TEAE, and 1 had a DLT, an asymptomatic grade-3 transaminitis). Twenty subjects received single-agent PY159 and 17 received PY159 in combination with pembrolizumab. Four subjects experienced a grade-3 TRAE, 14 a low-grade immune-related reaction, 18 an SAE (related in 2), and 14 an immune-related adverse event (arthralgias). There were no SUSARs. Five subjects sustained high-grade TRAE resulting in discontinuation. TREM1 levels in the tumors ranged from 0 to 15%. Pharmacokinetic parameters were linear beyond the 0.3 mg/kg dose, dose proportional with a half-life of 8–9 days, and unaffected by pembrolizumab. Radiographic response included 2 partial responses (1 each in an ovarian and pancreatic cancer subject) and stable disease in 9 subjects, ranging from 12 to 96+ weeks. Two subjects continue receiving PY159. Conclusions: PY159 was well tolerated, with an acceptable safety profile, as a single agent and in combination with pembrolizumab. A dose for expansion was derived and enrollment of subjects with 7 prespecified cancers is ongoing. Clinical trial information: NCT04682431 .
Retrospective analysis of digital biomarker predictability of immune checkpoint inhibitor therapy outcomes in patients with NSCLC.
Authors: Marin Abousaud, David Frame, R. Donald Harvey, Layan Kaddoura, Asari Ekpenyong, Aseala Abousaud, Conor Ernst Steuer, Brian Derstine, Nicholas C. Wang, Emily R. Mackler
Journal: Journal of Clinical Oncology (2023)

e14713 Background: Immune checkpoint inhibitor (ICI) therapy (pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy) is recommended as first line for patients with PD-L1 positive advanced or metastatic non-small cell lung cancer (NSCLC) without actionable biomarkers due to incredible improvements in overall survival (OS). Despite this, 15-20% of patients do not respond to ICI therapy in NSCLC. This study examines the effect of body composition features, via analytic morphomics, in conjunction with current clinical and laboratory data to predict ICI response. Methods: This retrospective analysis included 35 patients from the University of Michigan (UM) with newly diagnosed advanced or metastatic NSCLC (adenocarcinoma) receiving single-agent pembrolizumab or in combination with chemotherapy between January 2018 – December 2020. Clinical/ laboratory data included patient gender, age, BMI, neutrophil to lymphocyte ratio (NLR), PDL1 %, and albumin. Analytic Morphomics was performed using proprietary, semi-automated high-throughput CT image processing (mBIOHEALTH, Inc.). Multivariable Cox regression analysis identified clinical and morphomic characteristics predictive of OS at 6 months. Risk models were developed on the UM cohort and tested on an external validation dataset of 24 adenocarcinoma patients from Emory Healthcare who received similar treatment between January 2018 to December 2021. Results: Among the evaluable patients at both sites, 15 (43%) at UM and 19 (79%) at Emory were female, mean age was 66 years at UM and 70 years at Emory, and 6-month OS (95% CI) was 89% (80%, 100%) at UM and 71% (55%, 92%) at Emory. Five regression models with risk scores were assessed with the UM data and then tested with the Emory dataset. Of the five models, 2 matched in their predictability of 6-month OS at both sites. The first, a model of clinical and laboratory features only (age, BMI, PDL1 &gt; = 50%, NLR, and albumin) which had an AUC of 0.79 at UM and 0.66 at Emory. The other utilized an L3 skeletal muscle z-score threshold ( &lt; = -1) alone (previously studied as a measurement of sarcopenia) with an AUC of 0.741 at UM and 0.57 at Emory. Conclusions: Our analysis indicates that the measurement of muscle z-score prior to initiating treatment with ICIs in patients with NSCLC could serve as an indicator for those patients who are unlikely to benefit from therapy. This may be especially important for ICI therapy as skeletal muscle effects the immune function through myokines. Sarcopenia has been associated with immune senescence and thus may play a significant role in decreasing response to ICI therapy. More analysis is warranted with a larger patient population.
Outcomes in participants with a false positive multi-cancer early detection (MCED) test: Results from &gt;4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study.
Authors: Anne Marie Lennon, Adam H Buchanan, Seema P Rego, Omair A Choudhry, Paul Z Elias, Jennifer R Sadler, Joshua D Cohen, Christopher B Douville, Ashley M Honushefsky, Alison Klein, Zachary M Salvati, Kathleen Sheridan, Cristian Tomasetti, Eric S Wagner, Carroll N Walter, Elliot K. Fishman, Kenneth W. Kinzler, Bert Vogelstein, Tomasz M. Beer, Nickolas Papadopoulos
Journal: Journal of Clinical Oncology (2023)

3039 Background: Recommended standard of care (SOC) early detection tests are solely available for four cancer types and fewer than 20% of incident cancers in the US are being diagnosed as a result of screening. Advances in detection of tumor-derived analytes in the blood are enabling the development of MCED tests that may expand early cancer detection. While MCED tests are being designed with high specificity, false positive (FP) results remain a concern for clinicians and patients alike, as no long-term outcomes of individuals with a FP MCED test have been reported. DETECT-A was the first prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK, evaluated in 9,911 women without history of cancer ( Science, 369:6499, 2020). This prospectively planned analysis evaluates cancer incidence among DETECT-A participants with FP results, with the intention of providing key long-term data on test effectiveness. Methods: This analysis included 98 DETECT-A participants with FP results, where a FP was defined as a positive CancerSEEK result with subsequent PET-CT and clinical evaluation with no evidence of cancer within 1 year of the initial CancerSEEK test. Sixty-three of 98 participants had no follow-up procedure performed after imaging, and 35 subjects had noninvasive/minimally invasive follow-up procedures performed. Electronic medical records were analyzed from January 2020 through November 2022 for cancer diagnosis, treatment, remission, recurrence, and mortality. Results: Ninety-six of 98 participants with a FP result remained free of cancer with a median follow-up of 4.3 years (IQR: 3.9-4.9) from the initial CancerSEEK test. One stage I breast cancer and one stage III ovarian cancer were diagnosed 2.7 and 2.9 years respectively from the initial CancerSEEK test. Conclusions: Patients with a negative PET-CT and initial clinical evaluation after a positive CancerSEEK test had low (&lt;1% per year) risk for cancer in the ensuing four years after the initial CancerSEEK test. If confirmed, this result should prove reassuring to clinicians and to patients who have no evidence of cancer on comprehensive imaging following a positive MCED test. Further, these results provide preliminary support for the recommendation that patients who participate in MCED testing and receive a FP result can safely return to routine care after comprehensive anatomic and functional imaging and clinical evaluation reveal no suspicion of cancer.
Determinants of racial disparities in immune-related adverse events (irAE) with checkpoint inhibition (ICI) in melanoma.
Authors: Milad Ibrahim, Paola Angulo, Faisal Fa'ak, Noha Abdel-Wahab, Adi Diab, Janice M. Mehnert, Jeffrey S. Weber, Amanda Lund, Markus Schober, Judy Zhong, Iman Osman
Journal: Journal of Clinical Oncology (2023)

9549 Background: We recently reported that a pretreatment autoantibody (AutoAb) signature predicts immune-related adverse events (irAE) with an AUC of ~0.80 in melanoma patients enrolled in two phase III clinical trials of adjuvant ICI (Johannet et al. CCR 2022). The vast majority of those patients were non-Hispanic whites (NHW). We hypothesized that underrepresented minority (URM) melanoma patients might have a different baseline autoAb profile compared to NHW patients, as their site-specific irAEs differ ( Xue Bai et al. Br J of Derm 2022) and autoimmune disease is generally more common in underrepresented minorities (Roberts MH, Erdei E. Autoimmune Review 2020). We also explored the possibility that differences in the immuno-biology of acral melanoma (AM) and cutaneous melanoma (CM) – most commonly detected in URM and NHW patients, respectively – might inform our understanding of the racial differences in irAEs. Methods: We compared pre-treatment sera autoAb from URM melanoma patients (n=35) to NHW patients (n= 185) enrolled in Checkmate-238 (NCT02388906), Checkmate-915 (NCT03068455) or the NYU melanoma program database using the CDI and Sengenics proteomic platforms, and analyzed their association(s) with the development of grade 3-4 irAEs. We carried out single cell RNA-seq in AM versus CM tumor tissues to test whether expression of genes whose proteins were associated with irAE were preferentially expressed in AM tissue. We also compared RNA-seq of an immunoregulatory gene panel in AM versus CM tumors. Results: We identified autoAbs that were only detected in sera from URM patients with grade 3-4 irAEs (e.g. ALDOA, BANK1, LDHB and RNF7) and autoAbs that were only detected in NHW patients with grade 3-4 irAEs (e.g. GMEB2, YWHAE and ANKRD45). A subset of these autoAb targets was preferentially expressed in AM or CM tissues, while other targets were undetected in these melanoma subtypes. Cytokine signaling pathways were enriched in sera from URM but not NHW patients, and expression of genes known to modulate irAEs and response to ICI were significantly more expressed in AM than CM tumors, e.g. FOXP3 ( P=0.01), IL2 ( P=0.00547), IL4 ( P=0.0221) and IL10 ( P=0.0126). Conclusions: Our data suggest that URM patients have an altered tumor immune microenvironment that defines their response to ICI and risk of developing irAE. An integrative analysis of both the tumor and systemic immune environments is needed to better understand molecular links between response to ICI and irAEs in URM and NHW melanoma patients. A multi-center study is planned to address these questions.
Comparing the impact of steroid sparing immunosuppression vs. steroid monotherapy for immune-related adverse events in non–small cell lung cancer and melanoma.
Authors: Sharjeel Syed, Jacobi Hines, Rachel Baccile, Sherin Juliet Rouhani, Pankti Reid
Journal: Journal of Clinical Oncology (2023)

2637 Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.